Gene for the serotonin transporter and ADHD: No association with two functional polymorphisms

Abstract

Evidence from both human and animal studies implicates the serotonergic system in the development of attention-deficit hyperactivity disorder (ADHD) including positive association studies for several key serotonergic genes. The serotonin transporter (HTT) regulates the availability of serotonin by reuptake of the neurotransmitter from the synaptic cleft. Several studies have reported an association of this gene to ADHD, specifically the long variant of a common insertion/deletion polymorphism located in the promoter of this gene that results in increased transcription and higher HTT expression. An additional study found no evidence for an association with this polymorphism. Recently, an A/G single nucleotide polymorphism (SNP) was found within the promoter polymorphism with functional studies indicating that the long variant containing the G allele at this site behaves like the short variant. This previously unidentified functional change may have confounded earlier association studies. We investigated the relationship of several variants to ADHD: the promoter polymorphisms, SNP in the 3' untranslated region (3'UTR) with a reported association to ADHD and a rare, non-synonymous coding SNP. These polymorphisms were genotyped in 209 ADHD families identified through an affected proband. We did not find evidence for an association of these polymorphisms, or haplotypes of these polymorphisms, to ADHD in this sample.

Candidate gene studies of ADHD: a meta-analytic review

“…Ten TDT (Banerjee et al 2006;Heiser et al 2007;Kent et al 2002;Kim et al 2005a;Li et al 2007;Waldman et al unpublished data;Wigg et al 2006;Xu et al 2008Xu et al , 2005b and nine Case-Control/HHRR (Beitchman et al 2003;Curran et al 2005;Guimares et al 2007;Kopeckova et al 2008;Langley et al 2003;Manor et al 2001;Seeger et al 2001;Zhao et al 2005;Zoroglu et al 2002) studies were identiWed for the present meta-analysis of the association between childhood ADHD and the 5HTTLPR with the long variant designated as the "risk" allele. Results of this metaanalysis, shown in Fig.…”

“…Two TDT Wigg et al 2006) and three Case-Control/HHRR (Heiser et al 2007;Xu et al 2005b) studies were identiWed for the meta-analysis of the association between childhood ADHD and the 5HTT rs3813034 3ЈUTR SNP. The initial study testing this association reported preferential transmission of the "T" allele to ADHD probands in a sample of 113 children , and thus, the "T" allele was designated as the "risk" allele in the present meta-analysis.…”

Does serotonin deficit mediate susceptibility to ADHD?

“…In contrast two case-control (Kopecková et al, 2008, Xu et al, 2008 and three family based association studies (Banerjee et al, 2006, Heiser et al, 2007, Wigg et al, 2006, have reported negative association.…”

“…The association of G689T with ADHD has been previously examined in Caucasian and Asian populations (Banerjee et al, 2009, Curran et al, 2005, Heiser et al, 2007, Kent et al 2002, Wigg et al, 2006, Xu et al, 2005. In family-based studies Kent et al, reported significant (p=0.04) association of the T689 allele with ADHD cases (Kent et al 2002) which has not been confirmed by subsequent familybased (Banerjee et al, 2009, Heiser et al, 2007, Wigg et al, 2006, Xu et al, 2005 and case-control haploblock comprising rs6296, rs6297, rs130060, rs6298, rs130058 and rs11568817 is linked with the inattentive subtype of ADHD.…”

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder

“…In accord with these data two other studies found that short/short genotype was significantly underrepresented in children with ADHD compared to controls [Manor et al, 2001;Zorog lu et al, 2002]. However, Li et al [2007] reported a preferential transmission of the short-allele to ADHD offspring in a Chinese sample and six further studies did not find any association between the polymorphism and ADHD [Langley et al, 2003;Kim et al, 2005;Xu et al, 2005;Banerjee et al, 2006;Wigg et al, 2006;Heiser et al, 2007]. A study that combined the available data by pooling odds ratios across studies found a small but significant association of the long allele of 5-HTTLPR with ADHD [Faraone et al, 2005].…”